bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–05–04
fifty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
  2. Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
  3. The circadian clock at the intersection of metabolism and aging - emerging roles of metabolites.
  4. DPP8/9 processing of human AK2 unmasks an IAP binding motif.
  5. Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  6. TAMing immunity through an unexpected source.
  7. Starvation induces metabolic hepatocyte reprogramming.
  8. Unravelling the GIPR agonist versus antagonist paradox.
  9. NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
  10. Mitochondria - the CEO of the cell.
  11. The Lung Cancer Autochthonous Model Gene Expression Database Enables Cross-Study Comparisons of the Transcriptomic Landscapes Across Mouse Models.
  12. An atlas of ferroptosis-induced secretomes.
  13. Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
  14. NAD kinase essentiality in cancer: in real life, it is all about folates.
  15. SDH defective cancers: molecular mechanisms and treatment strategies.
  16. Aberrant basal cell clonal dynamics shape early lung carcinogenesis.
  17. Targeting CTP synthetase 1 to restore interferon induction and impede nucleotide synthesis in SARS-CoV-2 infection.
  18. Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
  19. Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.
  20. LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.
  21. Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
  22. IRF6 hits the sweet spot.
  23. Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
  24. Cell cycle duration determines oncogenic transformation capacity.
  25. Epithelial-to-mesenchymal transition drives cancer genomic instability.
  26. Large-Scale Metabolite Imaging Gallery of Mouse Organ Tissues to Study Spatial Metabolism.
  27. 4D mitochondrial network assumes distinct and predictive phenotypes through human lung and intestinal epithelial development.
  28. Cancer-Associated Cachexia: Bridging Clinical Findings with Mechanistic Insights in Human Studies.
  29. Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.
  30. Altering metabolism programs cell identity via NAD+-dependent deacetylation.
  31. Dissecting inflammation in the immunemetabolomic era.
  32. Ribosomal rebellion: When protein factories drive cancer progression.
  33. Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.
  34. The cell-division cycle is faster in cell types prone to forming cancer.
  35. Metabolic buffering suppresses phenotype switching in cancer.
  36. TRIB3 recruits and stabilizes CARM1 to confer chemoresistance by activating Akt signalling in clear cell renal cancer cells.
  37. Serum metabolite levels identify incipient metastatic progression of rectal cancer.
  38. 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
  39. Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division.
  40. The stochasticity of biological aging.
  41. STING: a multifaced player in cellular homeostasis.
  42. Activation of the Drosophila innate immune system accelerates growth in cooperation with oncogenic Ras.
  43. The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma.
  44. N-acetyl-l-cysteine averts ferroptosis by fostering glutathione peroxidase 4.
  45. Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
  46. This is not the new colour that scientists have created.
  47. Glucuronidation Metabolomic Fingerprinting to Map Host-Microbe Metabolism.
  48. Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis.
  49. p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer.
  50. Two highly specific growth-coupled biosensor for glycolaldehyde detection across micromolar and millimolar concentrations.
  51. Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.
  52. Isotope tracing-based metabolite identification for mass spectrometry metabolomics.
  53. B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8+ T cell function.
  54. Immune Resilience: Rewriting the Rules of Healthy Aging.
  55. Short-term aircraft noise stress induces a fundamental metabolic shift in heart proteome and metabolome that bears the hallmarks of cardiovascular disease.
  56. Microglia aging in the hippocampus advances through intermediate states that drive activation and cognitive decline.
  1. Nat Metab. 2025 Apr 28.
    Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
    Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.
      During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.
    DOI:  https://doi.org/10.1038/s42255-025-01289-8
  2. Nat Metab. 2025 May 02.
    Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
    Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.
      Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.
    DOI:  https://doi.org/10.1038/s42255-025-01272-3
  3. J Genet Genomics. 2025 Apr 28. pii: S1673-8527(25)00123-7. [Epub ahead of print]
    The circadian clock at the intersection of metabolism and aging - emerging roles of metabolites.
    Yue Dong, Sin Man Lam, Yan Li, Min-Dian Li, Guanghou Shui.
      The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops, which modulates an approximately 24-hour cycle of endocrine and metabolic rhythms within cells and tissues. While circadian clocks regulate metabolic processes and related physiology, emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined. In this review, we highlight the concept of metabolites, including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake, as circadian pacemakers that drive changes in circadian rhythms, which in turn influence metabolism and aging. Furthermore, we discuss the roles of functional metabolites as circadian pacemakers, paving a new direction on potential intervention targets of circadian disruption, pathological aging, as well as metabolic diseases that are clinically important.
    Keywords:  Aging; Circadian clock; Metabolic diseases; Metabolites; Pacemakers
    DOI:  https://doi.org/10.1016/j.jgg.2025.04.014
  4. EMBO Rep. 2025 May 01.
    DPP8/9 processing of human AK2 unmasks an IAP binding motif.
    Kim J Lapacz, Konstantin Weiss, Franziska Mueller, Yuxing Xue, Simon Poepsel, Matthias Weith, Tanja Bange, Jan Riemer.
      Adenylate kinase 2 (AK2) is localized in the intermembrane space of mitochondria, where it ensures efficient adenine nucleotide exchange between cytosol and mitochondria. For mitochondrial import, AK2 relies on the MIA40 disulphide relay system. Its cytosolic stability is subject to regulation through N-terminal processing by the dipeptidyl peptidases DPP8 and DPP9, which sensitize AK2 for proteasomal degradation. Here, we find that cytosolic AK2 degradation is mediated by Inhibitors of Apoptosis (IAPs), a class of E3 ligases that interacts with target proteins by binding to IAP-binding motifs (IBM). We have identified an IBM at the very end of AK2's novel N-terminus, which becomes exposed due to processing by DPP8/9. N-terminal acetylation mediated by the N-acetyltransferase NatA prevents this AK2-IAP interaction, therefore stabilizing AK2 in the cytosol. Performing a genome-wide in silico screen, we could identify 129 potential substrates in which an IBM becomes potentially unmasked by DPP8/9 processing. For one of these potential substrates, EIF2A, we demonstrate its targeting to IAPs after IBM exposure by DPP8/9 indicating that DPP8/9-mediated unmasking of IBMs is a general phenomenon.
    Keywords:  AK2; DPP9; IAP‐binding Motif; Inhibitor of Apoptosis (IAP) Proteins; N-terminal Acetylation
    DOI:  https://doi.org/10.1038/s44319-025-00455-z
  5. Nat Commun. 2025 Apr 29. 16(1): 4029
    Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.
    DOI:  https://doi.org/10.1038/s41467-025-59427-5
  6. Cancer Cell. 2025 Apr 22. pii: S1535-6108(25)00163-1. [Epub ahead of print]
    TAMing immunity through an unexpected source.
    Ian Vogel, Sagar P Bapat.
      Arginine availability and metabolism critically shape tumor-immune interactions. In this issue of Cancer Cell, Zhu et al. demonstrate that breast cancer-cell-derived arginine synthesized via ASS1 fuels macrophage polyamine synthesis, reinforcing immunosuppressive tumor-associated macrophages (TAMs). Mechanistically, this occurs through TDG/p53-dependent DNA demethylation and activation of PPARG.
    DOI:  https://doi.org/10.1016/j.ccell.2025.04.004
  7. Nat Metab. 2025 Apr 25.
    Starvation induces metabolic hepatocyte reprogramming.
    Coenraad F Slabber, Jan S Tchorz.
      
    DOI:  https://doi.org/10.1038/s42255-025-01286-x
  8. Nat Metab. 2025 Apr 29.
    Unravelling the GIPR agonist versus antagonist paradox.
    Alice E Adriaenssens.
      
    DOI:  https://doi.org/10.1038/s42255-025-01299-6
  9. Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]
    NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
    Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.
      Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
    Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
  10. J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):
    Mitochondria - the CEO of the cell.
    Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.
      As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.
    Keywords:  Mitochondria; Organelle; mtDNA
    DOI:  https://doi.org/10.1242/jcs.263403
  11. Cancer Res. 2025 Apr 29. OF1-OF15
    The Lung Cancer Autochthonous Model Gene Expression Database Enables Cross-Study Comparisons of the Transcriptomic Landscapes Across Mouse Models.
    Ling Cai, Fangjiang Wu, Qinbo Zhou, Ying Gao, Bo Yao, Ralph J DeBerardinis, George K Acquaah-Mensah, Vassilis Aidinis, Jennifer E Beane, Shyam Biswal, Ting Chen, Carla P Concepcion-Crisol, Barbara M Grüner, Deshui Jia, Robert A Jones, Jonathan M Kurie, Min Gyu Lee, Per Lindahl, Yonathan Lissanu, Corina Lorz, David MacPherson, Rosanna Martinelli, Pawel K Mazur, Sarah A Mazzilli, Shinji Mii, Herwig P Moll, Roger A Moorehead, Edward E Morrisey, Sheng Rong Ng, Matthew G Oser, Arun R Pandiri, Charles A Powell, Giorgio Ramadori, Mirentxu Santos, Eric L Snyder, Rocio Sotillo, Kang-Yi Su, Tetsuro Taki, Kekoa Taparra, Phuoc T Tran, Yifeng Xia, J Edward van Veen, Monte M Winslow, Guanghua Xiao, Charles M Rudin, Trudy G Oliver, Yang Xie, John D Minna.
      Lung cancer, the leading cause of cancer mortality, exhibits diverse histologic subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. In this study, we established the Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMM), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCAMGDB aligned 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in the GEMMs. To accompany this resource, a web application was developed that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCAMGDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance. Significance: The Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB) provides a comprehensive and accessible resource for the research community to investigate lung cancer biology in mouse models.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1607
  12. Cell Death Differ. 2025 Apr 25.
    An atlas of ferroptosis-induced secretomes.
    F Isil Yapici, Eric Seidel, Alina Dahlhaus, Josephine Weber, Christina Schmidt, Adriano de Britto Chaves Filho, Ming Yang, Maria Nenchova, Emre Güngör, Jenny Stroh, Ioanna Kotouza, Julia Beck, Ali T Abdallah, Jan-Wilm Lackmann, Christina M Bebber, Ariadne Androulidaki, Peter Kreuzaler, Almut Schulze, Christian Frezza, Silvia von Karstedt.
      Cells undergoing regulated necrosis systemically communicate with the immune system via the release of protein and non-protein secretomes. Ferroptosis is a recently described iron-dependent type of regulated necrosis driven by massive lipid peroxidation. While membrane rupture occurs during ferroptosis, a comprehensive appraisal of ferroptotic secretomes and their potential biological activity has been lacking. Here, we apply a multi-omics approach to provide an atlas of ferroptosis-induced secretomes and reveal a novel function in macrophage priming. Proteins with assigned DAMP and innate immune system function, such as MIF, heat shock proteins (HSPs), and chaperones, were released from ferroptotic cells. Non-protein secretomes with assigned inflammatory function contained oxylipins as well as TCA- and methionine-cycle metabolites. Interestingly, incubation of bone marrow-derived macrophages (BMDMs) with ferroptotic supernatants induced transcriptional reprogramming consistent with priming. Indeed, exposure to ferroptotic supernatants enhanced LPS-induced cytokine production. These results define a catalog of ferroptosis-induced secretomes and identify a biological activity in macrophage priming with important implications for the fine-tuning of inflammatory processes.
    DOI:  https://doi.org/10.1038/s41418-025-01517-4
  13. Cell Metab. 2025 Apr 25. pii: S1550-4131(25)00217-7. [Epub ahead of print]
    Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
    Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Jeffrey Milbrandt, David K Imagawa, Dorota Skowronska-Krawczyk, Danica Chen, Gina Lee, Cholsoon Jang, Qin Yang.
      Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD+ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.
    Keywords:  NAD(+); aging; kidney; liver; nicotinic acid riboside
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.007
  14. Nat Metab. 2025 May 02.
    NAD kinase essentiality in cancer: in real life, it is all about folates.
    Petra Marttila, Johannes Meiser.
      
    DOI:  https://doi.org/10.1038/s42255-025-01270-5
  15. Cell Biol Toxicol. 2025 Apr 26. 41(1): 74
    SDH defective cancers: molecular mechanisms and treatment strategies.
    Jiaer Wang, Tao Yuan, Bo Yang, Qiaojun He, Hong Zhu.
      Succinate dehydrogenase (SDH), considered as the linkage between tricarboxylic acid cycle (TCA cycle) and electron transport chain, plays a vital role in adenosine triphosphate (ATP) production and cell physiology. SDH deficiency is a notable characteristic in many cancers. Recent studies have pinpointed the dysregulation of SDH can directly result its decreased catalytic activity and the accumulation of oncometabolite succinate, promoting tumor progression in different perspectives. This article expounds the various types of SDH deficiency in tumors and the corresponding pathological features. In addition, we discuss the mechanisms through which defective SDH fosters carcinogenesis, pioneering a categorization of these mechanisms as being either succinate-dependent or independent. Since SDH-deficient and cumulative succinate are regarded as the typical features of some cancers, like gastrointestinal stromal tumors, pheochromocytomas and paragangliomas, we summarize the presented medical management of SDH-deficient tumor patients in clinical and preclinical, identifying the potential strategies for future cancer therapeutics.
    Keywords:  Mechanism; Medical management; SDH-deficient cancer; Succinate
    DOI:  https://doi.org/10.1007/s10565-025-10022-w
  16. Science. 2025 May 01. eads9145
    Aberrant basal cell clonal dynamics shape early lung carcinogenesis.
    Sandra Gómez-López, Ahmed S N Alhendi, Moritz J Przybilla, Ignacio Bordeu, Zoe E Whiteman, Timothy Butler, Maral J Rouhani, Lukas Kalinke, Imran Uddin, Kate E J Otter, Deepak P Chandrasekharan, Marta Lebrusant-Fernandez, Abigail Y L Shurr, Pascal F Durrenberger, David A Moore, Mary Falzon, James L Reading, Iñigo Martincorena, Benjamin D Simons, Peter J Campbell, Sam M Janes.
      Preinvasive squamous lung lesions are precursors of lung squamous cell carcinoma (LUSC). The cellular events underlying lesion formation are unknown. Using a carcinogen-induced model of LUSC with no added genetic hits or cell type bias, we find that carcinogen exposure leads to non-neutral competition among basal cells, aberrant clonal expansions, and basal cell mobilization along the airways. Ultimately, preinvasive lesions develop from a few highly mutated clones that dominate most of the bronchial tree. Multi-site sequencing in human patients confirms the presence of clonally related preinvasive lesions across distinct airway regions. Our work identifies a transition in basal cell clonal dynamics, and an associated shift in basal cell fate, as drivers of field cancerization in the lung.
    DOI:  https://doi.org/10.1126/science.ads9145
  17. mBio. 2025 Apr 29. e0064925
    Targeting CTP synthetase 1 to restore interferon induction and impede nucleotide synthesis in SARS-CoV-2 infection.
    Youliang Rao, Chao Qin, Bianca Espinosa, Ting-Yu Wang, Shu Feng, Ali Can Savas, Jill Henley, Lucio Comai, Chao Zhang, Pinghui Feng.
      Despite the global impact caused by the most recent SARS-CoV-2 pandemic, our knowledge of the molecular underpinnings of its highly infectious nature remains incomplete. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. In addition to catalyzing CTP synthesis, CTPS1 also deamidates interferon regulatory factor 3 (IRF3) to dampen interferon induction. Screening a SARS-CoV-2 expression library, we identified several viral proteins that interact with CTPS1. Functional analyses demonstrate that ORF8 and Nsp8 activate CTPS1 to deamidate IRF3 and negate IFN induction, whereas ORF7b and ORF8 activate CTPS1 to promote CTP synthesis. These results highlight CTPS1 as a signaling node that integrates cellular metabolism and innate immune response. Indeed, small-molecule inhibitors of CTPS1 deplete CTP and boost IFN induction in SARS-CoV-2-infected cells, thus effectively impeding SARS-CoV-2 replication and pathogenesis in mouse models. Our work uncovers an intricate mechanism by which a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means to develop antiviral therapy against highly mutagenic viruses.IMPORTANCEOur understanding of the underpinnings of highly infectious SARS-CoV-2 is rudimentary at best. We report here that SARS-CoV-2 activates CTPS1 to promote CTP synthesis and suppress IFN induction, thus coupling immune evasion to activated nucleotide synthesis. Inhibition of the key metabolic enzyme not only depletes the nucleotide pool but also boosts host antiviral defense, thereby impeding SARS-CoV-2 replication. Targeting cellular enzymes presents a strategy to counter the rapidly evolving SARS-CoV-2 variants.
    Keywords:  CTPS1; SARS-CoV-2; antiviral pharmacology; interferon; pyrimidine metabolism
    DOI:  https://doi.org/10.1128/mbio.00649-25
  18. EMBO Rep. 2025 Apr 29.
    Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
    Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.
      Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.
    Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1
    DOI:  https://doi.org/10.1038/s44319-025-00459-9
  19. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00398-5. [Epub ahead of print]44(5): 115627
    Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.
    Jillian S Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z Stanger, Anil K Rustgi, Jason R Pitarresi, J Kevin Foskett.
      Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.
    Keywords:  CP: Cancer; CP: Metabolism; EMT; MCU; PDAC; calcium signaling; cancer; epithelial-to-mesenchymal transition; metabolism; mitochondria; pancreas; uniporter
    DOI:  https://doi.org/10.1016/j.celrep.2025.115627
  20. Nat Commun. 2025 May 02. 16(1): 4112
    LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.
    Chendi Li, Mohammed Usman Syed, Anahita Nimbalkar, Yi Shen, Melissa D Vieira, Cameron Fraser, Zintis Inde, Xingping Qin, Jian Ouyang, Johannes Kreuzer, Sarah E Clark, Grace Kelley, Emily M Hensley, Robert Morris, Raul Lazaro, Brian Belmonte, Audris Oh, Makeba Walcott, Christopher S Nabel, Sean Caenepeel, Anne Y Saiki, Karen Rex, J Russell Lipford, Rebecca S Heist, Jessica J Lin, Wilhelm Haas, Kristopher Sarosiek, Paul E Hughes, Aaron N Hata.
      The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.
    DOI:  https://doi.org/10.1038/s41467-025-58753-y
  21. Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]
    Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
    Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.
      Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.
    Keywords:  CCN1; cell death; mitochondria
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
  22. Cell Stem Cell. 2025 May 01. pii: S1934-5909(25)00137-7. [Epub ahead of print]32(5): 671-672
    IRF6 hits the sweet spot.
    Jane Reznick, Carien M Niessen.
      Glucose serves as an essential energy source for cells. In this issue, Lopez-Pajares et al.1 uncover a role for glucose uncoupled from its energetic function. During epidermal differentiation, free glucose accumulates and binds the pro-differentiation transcription factor IRF6, promoting its dimerization and DNA binding to activate genes that drive differentiation.
    DOI:  https://doi.org/10.1016/j.stem.2025.04.002
  23. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251332141
    Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
    Jason C Casler, Matilde V Neto, Thomas Burgoyne, Laura L Lackner.
      Sites of close apposition between organelles, known as membrane contact sites (MCSs), are critical regulators of organelle function. Mitochondria form elaborate reticular networks that perform essential metabolic and signaling functions. Many mitochondrial functions are regulated by MCSs formed between mitochondria and other organelles. In this review, we aim to bring attention to an understudied, but physiologically important, MCS between mitochondria and the plasma membrane (PM). We first describe the molecular mechanism of mitochondria-PM tethering in budding yeast and discuss its role in regulating multiple biological processes, including mitochondrial dynamics and lipid metabolism. Next, we discuss the evidence for mitochondria-PM tethering in higher eukaryotes, with a specific emphasis on mitochondria-PM contacts in retinal cells, and speculate on their functions. Finally, we discuss unanswered questions to guide future research into the function of mitochondria-PM contact sites.
    Keywords:  cell biology; electron microscopy; interorganelle (inter-organelle); membrane contact sites (MCSs)‌; mitochondrion (mitochondria); plasma membrane
    DOI:  https://doi.org/10.1177/25152564251332141
  24. Nature. 2025 Apr 30.
    Cell cycle duration determines oncogenic transformation capacity.
    Danian Chen, Suying Lu, Katherine Huang, Joel D Pearson, Marek Pacal, Phillipos Peidis, Sean McCurdy, Tao Yu, Monika Sangwan, Angela Nguyen, Philippe P Monnier, Daniel Schramek, Liang Zhu, David Santamaria, Mariano Barbacid, Nagako Akeno, Kathryn A Wikenheiser-Brokamp, Rod Bremner.
      Oncogenic mutations are widespread in normal human tissues1. Similarly, in murine chimeras, cells carrying an oncogenic lesion contribute normal cells to adult tissues without causing cancer2-4. How lineages that escape cancer via normal development differ from the minority that succumb is unclear. Tumours exhibit characteristic cancer hallmarks; we therefore searched for hallmarks that differentiate cancer-prone lineages from resistant lineages. Here we show that total cell cycle duration (Tc) predicts transformation susceptibility across multiple tumour types. Cancer-prone Rb- and p107-deficient retina (Rb is also known as Rb1 and p107 is also known as Rbl1) exhibited defects in apoptosis, senescence, immune surveillance, angiogenesis, DNA repair, polarity and proliferation. Perturbing the SKP2-p27-CDK2/CDK1 axis could block cancer without affecting these hallmarks. Thus, cancer requires more than the presence of its hallmarks. Notably, every tumour-suppressive mutation that we tested increased Tc, and the Tc of the cell of origin of retinoblastoma cells was half that of resistant lineages. Tc also differentiated the cell of origin in Rb-/- pituitary cancer. In lung, loss of Rb and p53 (also known as Trp53) transforms neuroendocrine cells, whereas KrasG12D or BrafV600E mutations transform alveolar type 2 cells5-7. The shortest Tc consistently identified the cell of origin, regardless of mutation timing. Thus, relative Tc is a hallmark of initiation that distinguishes cancer-prone from cancer-resistant lineages in several settings, explaining how mutated cells escape transformation without inducing apoptosis, senescence or immune surveillance.
    DOI:  https://doi.org/10.1038/s41586-025-08935-x
  25. J Exp Clin Cancer Res. 2025 Apr 30. 44(1): 135
    Epithelial-to-mesenchymal transition drives cancer genomic instability.
    Julienne L Carstens, Sara Lovisa.
      Epithelial-to-Mesenchymal Transition (EMT) is a form of embryonic cell plasticity reactivated in adult cells during injury and cancer. A recent study by Perelli et al. demonstrates that EMT confers an evolutionary advantage to tumors by inducing chromosomal instability, structural genomic rearrangements and chromothripsis, thus favoring the emergence of high-fitness malignant clones.
    Keywords:  Cancer; Cell plasticity; EMT; Epithelial-to-mesenchymal transition; Genomic instability
    DOI:  https://doi.org/10.1186/s13046-025-03402-x
  26. J Proteome Res. 2025 Apr 28.
    Large-Scale Metabolite Imaging Gallery of Mouse Organ Tissues to Study Spatial Metabolism.
    Karl W Smith, Antonia Fecke, Siva Swapna Kasarla, Prasad Phapale.
      Mass spectrometry imaging (MSI) has revolutionized the study of tissue metabolism by enabling the visualization of small molecule metabolites (SMMs) with high spatial resolution. However, comprehensive SMM imaging databases for different organ tissues are lacking, hindering our understanding of spatial organ metabolism. To address this resource gap, we present a large-scale SMM imaging gallery for mouse brain, kidney, and liver, capturing SMMs spanning eight chemical super classes and encompassing over 40 metabolic pathways. Manual curation and display of these imaging data sets unveil spatial patterns of metabolites that are less documented in the reported organs. Specifically, we identify 65 SMMs in brain coronal sections and 71 in sagittal tissue sections, including spatial patterns for neurotransmitters. Furthermore, we map 98 SMMs in kidneys and 66 SMMs in liver, providing insights into their amino acid and glutathione metabolism. Our insightful SMM imaging gallery serves as a critical resource for the spatial metabolism research community, filling a significant resource gap. This resource is freely available for download and can be accessed through the BioImage Archive and METASPACE repositories, providing high-quality annotated images for potential future computational models and advancing our understanding of tissue metabolism at the spatial level.
    Keywords:  MALDI-MSI; imaging database; mass spectrometry imaging; metabolite imaging; organ metabolism; small molecules; spatial metabolomics; tissue metabolism
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00594
  27. bioRxiv. 2025 Apr 10. pii: 2025.04.09.648043. [Epub ahead of print]
    4D mitochondrial network assumes distinct and predictive phenotypes through human lung and intestinal epithelial development.
    Gillian McMahon, Dhruv Agarwal, Mehul Arora, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg.
      Mitochondria form a dynamic three-dimensional network within the cell that exhibits a wide range of morphologies and behaviors. Depending on cell state, cell type, and cell fate, a cell's mitochondrial phenotype might range from relatively isolated mitochondrial segments to complex branching networks, and from stationary mitochondria to highly motile structures. While isolated mitochondrial phenotypes have been described for a subset of cell states, types, and fates, an integrated map of how mitochondrial phenotypes change over the full course of tissue development has so far been lacking. Here, we identify the mitochondrial phenotypes that appear throughout the course of lung and intestinal epithelial development from stem cells to differentiated tissue. Using human stem cell-derived intestinal and branching lung organoids that mimic developing human organs as model systems, we extract and analyze key mitochondrial biophysical phenotypes in human development. To achieve this, we employ lattice light-sheet microscopy (LLSM), which enables high-resolution, 4D (x, y, z, time) imaging of mitochondria in organoid tissues with minimal damage to the sample. We image at key developmental time points from stem cell differentiation into mature organoid tissue. For data processing, we utilize the MitoGraph and MitoTNT software packages along with our developed custom computational tools. These tools allow for automated 4D organoid to single cell image processing and quantitative 4D single cell mitochondrial temporal network tracking. This work represents the first 4D high spatiotemporal-resolution quantification of live human organoid tissues at the single-cell level through development. We identified distinct mitochondrial phenotypes unique to each organoid type and found correlations between mitochondrial phenotypes, cellular age, and cell type. Furthermore, we demonstrate that mitochondrial network characteristics can predict both organoid type and cell age. Our findings reveal fundamental aspects of mitochondrial biology that were previously unobservable, offering new insights into cell-type-specific mitochondrial dynamics and enabling new findings in relevant human model systems. We believe that our findings and methods will be essential for advancing 4D cell biology, providing a powerful framework for characterizing organelles in organoid tissues.
    DOI:  https://doi.org/10.1101/2025.04.09.648043
  28. Cancer Discov. 2025 Apr 29. OF1-OF26
    Cancer-Associated Cachexia: Bridging Clinical Findings with Mechanistic Insights in Human Studies.
    Kexin Koh, Rachel Scott, Elizabeth M Cespedes Feliciano, Tobias Janowitz, Marcus D Goncalves, Eileen P White, Barry J A Laird, Kerstin Haase, Mariam Jamal-Hanjani.
       SIGNIFICANCE: CAC represents a significant clinical unmet need. Despite its high prevalence and associated mortality and morbidity, there are currently no globally approved effective therapies. This review provides a comprehensive overview of human studies aimed at defining CAC clinically and identifying mediators underlying it that are revealing effective health interventions. Furthermore, we highlight ongoing international efforts to advance our understanding of CAC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0293
  29. Cancer Discov. 2025 Apr 28. OF1-OF18
    Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.
    Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa de Stanchina, Scott W Lowe, Richard A Burkhart, Jacquelyn W Zimmerman, Rona Yaeger, Scott E Kopetz, Neal Rosen, Sandra Misale.
       SIGNIFICANCE: RAS inhibition in multiple tumor types reveals the difference between G12 mutants and Q61 mutants in their cooperation with upstream regulators and downstream effectors to promote oncogenic signaling. Our findings provide the rationale for combinatorial approaches and contribute to explaining the nonuniform distribution of RAS mutations, de novo and at resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0614
  30. EMBO J. 2025 Apr 25.
    Altering metabolism programs cell identity via NAD+-dependent deacetylation.
    Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, Joshua M Brickman.
      Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.
    Keywords:  Aging; Enhancers; Metabolism; Pluripotency; Sirtuins
    DOI:  https://doi.org/10.1038/s44318-025-00417-0
  31. Cell Mol Life Sci. 2025 Apr 28. 82(1): 182
    Dissecting inflammation in the immunemetabolomic era.
    Patricia P Ogger, Peter J Murray.
      The role of immune metabolism, specific metabolites and cell-intrinsic and -extrinsic metabolic states across the time course of an inflammatory response are emerging knowledge. Targeted and untargeted metabolomic analysis is essential to understand how immune cells adapt their metabolic program throughout an immune response. In addition, metabolomic analysis can aid to identify pathophysiological patterns in inflammatory disease. Here, we discuss new metabolomic findings within the transition from inflammation to resolution, focusing on three key programs of immunity: Efferocytosis, IL-10 signaling and trained immunity. Particularly the tryptophan-derived metabolite kynurenine was identified as essential for efferocytosis and inflammation resolution as well as a potential biomarker in diverse inflammatory conditions. In summary, metabolomic analysis and integration with transcriptomic and proteomic data, high resolution imaging and spatial information is key to unravel metabolic drivers and dependencies during inflammation and progression to tissue-repair.
    Keywords:  Chronic inflammatory disease; Efferocytosis; IL-10; Kynurenine; Metabolomics; Spatial resolution; Trained immunity
    DOI:  https://doi.org/10.1007/s00018-025-05715-8
  32. Cancer Cell. 2025 Apr 18. pii: S1535-6108(25)00136-9. [Epub ahead of print]
    Ribosomal rebellion: When protein factories drive cancer progression.
    Qiushuang Wu, Sohail F Tavazoie.
      In Cancer Cell, two studies unveil mechanisms by which co-option of the protein synthesis machinery promotes cancer progression and potential therapeutic interventions. Kuzuoglu-Ozturk et al. show that eIF4A-mediated enhancement of oncogenic transcript translation initiation drives cancer progression, while Weller et al. demonstrate how aberrant transfer RNA (tRNA) modification disrupts translational fidelity to produce neoantigens.
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.035
  33. Nat Rev Genet. 2025 Apr 25.
    Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.
    Diane D Shao, Andrea J Kriz, Daniel A Snellings, Zinan Zhou, Yifan Zhao, Liz Enyenihi, Christopher Walsh.
      DNA sequencing from bulk or clonal human tissues has shown that genetic mosaicism is common and contributes to both cancer and non-cancerous disorders. However, single-cell resolution is required to understand the full genetic heterogeneity that exists within a tissue and the mechanisms that lead to somatic mosaicism. Single-cell DNA-sequencing technologies have traditionally trailed behind those of single-cell transcriptomics and epigenomics, largely because most applications require whole-genome amplification before costly whole-genome sequencing. Now, recent technological and computational advances are enabling the use of single-cell DNA sequencing to tackle previously intractable problems, such as delineating the genetic landscape of tissues with complex clonal patterns, of samples where cellular material is scarce and of non-cycling, postmitotic cells. Single-cell genomes are also revealing the mutational patterns that arise from biological processes or disease states, and have made it possible to track cell lineage in human tissues. These advances in our understanding of tissue biology and our ability to identify disease mechanisms will ultimately transform how disease is diagnosed and monitored.
    DOI:  https://doi.org/10.1038/s41576-025-00832-3
  34. Nature. 2025 Apr 30.
    The cell-division cycle is faster in cell types prone to forming cancer.
    Helen K Matthews.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-01138-4
  35. bioRxiv. 2025 Apr 12. pii: 2025.04.07.647576. [Epub ahead of print]
    Metabolic buffering suppresses phenotype switching in cancer.
    Ana Ramírez-Sánchez, Miguel Jociles-Ortega, José Manuel García-Martinez, Irene Torrens-Martínez, Javier Martínez-Useros, María Jesús Fernández-Aceñero, Teresa Olmos-De Blas, Pakavarin Louphrasitthiphol, Colin R Goding, Custodia García-Jiménez, Ana Chocarro-Calvo.
      The impact of the microenvironment on epigenetically plastic cancer cells underpins phenotypic heterogeneity, a major cause of metastatic dissemination and therapy resistance that together represent the primary cause of cancer-related death. Nutrient limitation is a key microenvironmental stress that can cause a phenotypic transition from proliferation to invasion via activation of the integrated stress response. However, whether and how the capacity to store and mobilize nutrients impacts phenotype-switching through metabolic buffering remains unknown. Here, using melanoma as a model, we reveal that the ability to accumulate and mobilize glycogen, that buffers glucose availability, plays a key role in phenotypic transitions in melanoma. While proliferative phenotype cells exhibit high levels of glycogen, invasion is marked by low glycogen levels. Significantly, an inability to store and metabolize glycogen leads to phenotype instability and a switch to invasion. Accordingly, glycogen levels inversely correlate with Clark levels in primary melanomas, with low expression of the glycogen phosphorylases PYGB/L and phosphoglucomutase 1 (PGM1) being associated with worse overall survival. The importance of metabolic buffering in suppressing phenotypic transitions likely extrapolates to other cancer types.
    Highlights: Melanoma phenotypes are distinguished by their ability to store and mobilize glycogen. Proliferative MITF High melanoma cells store glycogen to improve survival under stressful conditions. Inhibition of glycogen degradation impairs proliferation in MITF High melanoma cells. Lack of PGM1 drives invasion and metastatic dissemination.
    DOI:  https://doi.org/10.1101/2025.04.07.647576
  36. Biochem Biophys Res Commun. 2025 Apr 15. pii: S0006-291X(25)00541-8. [Epub ahead of print]766 151827
    TRIB3 recruits and stabilizes CARM1 to confer chemoresistance by activating Akt signalling in clear cell renal cancer cells.
    Danfei Hu, Xiaodong Fan, Xiaodong Chen, Mingyao Li, Huacai Xiong, Xiaoxiao Fan, Feng Chen.
      Sunitinib resistance remains a major obstacle in the treatment of clear cell renal cell carcinoma (ccRCC), yet the underlying mechanisms are poorly defined. Here, we identify a previously unrecognized axis involving Tribbles homolog 3 (TRIB3) and coactivator-associated arginine methyltransferase 1 (CARM1) that drives chemoresistance through modulation of Akt signaling. Mechanistically, TRIB3 directly interacts with CARM1, a pro-survival epigenetic regulator, and inhibits its ubiquitination to stabilize CARM1 protein levels. Elevated CARM1 further exacerbates therapeutic resistance, establishing a feedforward loop that sustains Akt activation. Our findings uncovering a novel TRIB3-CARM1-Akt axis as a central driver of sunitinib resistance. This study provides mechanistic insights into ccRCC chemoresistance and highlights therapeutic targeting of the TRIB3-CARM1 axis as a promising strategy to overcome treatment failure.
    Keywords:  Akt; CARM1; Sunitinib; TRIB3; ccRCC
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151827
  37. Commun Med (Lond). 2025 Apr 27. 5(1): 142
    Serum metabolite levels identify incipient metastatic progression of rectal cancer.
    Kine M Bakke, Paula A Bousquet, Sebastian Meltzer, Tonje Bjørnetrø, Frode Rise, Alistair L Wilkins, Kathrine Røe Redalen, Anne Hansen Ree.
       BACKGROUND: The cellular metabolism undergoes reprogramming during the metastatic process. We hypothesised that serum metabolites at the time of primary tumour diagnosis might identify rectal cancer patients prone to metastatic progression.
    METHODS: One hundred twenty-three rectal cancer patients from a prospective observational biomarker study were followed up to 5 years after study entry. We have assessed metabolites in serum sampled at the time of diagnosis by 1H-nuclear magnetic resonance spectroscopy, using the internal reference trimethylsilylpropanoic acid for quantification.
    RESULTS: Here we show that patients who develop overt metastatic disease more than 6 months after the primary tumour diagnosis have elevated serum levels (Kruskal-Wallis test) of alanine (P = 0.005), lactate (P = 0.023), pyruvate (P = 0.041) and citrate (P = 0.007) compared to those without metastases at the 5-year follow-up or with metastases already 6 months or sooner after the cancer diagnosis. Patients with serum citrate above 0.24 mmol/L have poorer progression-free survival compared to those with levels below (P < 0.001; log-rank test).
    CONCLUSIONS: We observe a distinct serum metabolite profile, in particular involving citrate to the best of our knowledge shown for the first time clinically, in rectal cancer patients at heightened risk of metastasis already when the primary tumour is diagnosed, offering insights into the metabolism of metastatic progression.
    DOI:  https://doi.org/10.1038/s43856-025-00868-w
  38. Aging Cell. 2025 Apr 25. e70054
    3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
    Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton.
      Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.
    Keywords:  3D reconstruction; MFN‐2; aging; exercise; human skeletal muscle; mitochondria
    DOI:  https://doi.org/10.1111/acel.70054
  39. Nat Commun. 2025 Apr 26. 16(1): 3932
    Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division.
    Hien Bui, Simon Andersson, Agustin Sola-Carvajal, Tommaso De Marchi, Eliisa Vähäkangas, Minna Holopainen, Andrew H House, Bohdana M Rovenko, Johanna I Englund, Maria Kasper, Emilia Kuuluvainen, Reijo Käkelä, Ville Hietakangas, Emma Niméus, Pekka Katajisto.
      Selective inheritance of sub-cellular components has emerged as a mechanism guiding stem cell fate after asymmetric cell divisions. Peroxisomes play a crucial role in multiple metabolic processes such as fatty acid metabolism and reactive oxygen species detoxification, but the apportioning of peroxisomes during stem cell division remains understudied. Here, we develop a mouse model and labeling technique to follow the dynamics of distinct peroxisome age-classes, and find that old peroxisomes are inherited by the daughter cell retaining full stem cell potency in mammary and epidermal stem cell divisions. Old peroxisomes carry Glucose-6-phosphate-dehydrogenase, whose specific location on the peroxisomal membrane promotes stem cell function by facilitating peroxisomal ether lipid synthesis. Our study demonstrates age-selective apportioning of peroxisomes in vivo, and unveils how functional heterogeneity of peroxisomes is utilized by asymmetrically dividing cells to metabolically divert the fate of the two daughter cells.
    DOI:  https://doi.org/10.1038/s41467-025-58752-z
  40. Nat Med. 2025 Apr 29.
    The stochasticity of biological aging.
    David H Meyer, Björn Schumacher.
      
    DOI:  https://doi.org/10.1038/s41591-025-03687-7
  41. Hum Mol Genet. 2025 Apr 28. pii: ddae175. [Epub ahead of print]
    STING: a multifaced player in cellular homeostasis.
    Kun Song, Lyu Heng, Nan Yan.
      The stimulator of interferon gene (STING) is an important innate immune mediator of the cytoplasmic DNA sensing pathway. As a mediator known for its role in the immune response to infections, STING is also surprisingly at the center of a variety of non-infectious human diseases, including cancer, autoimmune diseases and neurodegenerative diseases. Recent studies have shown that STING has many signaling activities, including type I interferon (IFN-I) and other IFN-independent activities, many of which are poorly understood. STING also has the unique property of being continuous transported from the ER to the Golgi then to the lysosome. Mutations of STING or trafficking cofactors are associated with human diseases affecting multiple immune and non-immune organs. Here, we review recent advances in STING trafficking and signaling mechanisms based in part on studies of STING-associated monogenic inborn error diseases.
    Keywords:  STING; autoimmune diseases; neurodegenerative disease; type I interferon; vesicle trafficking
    DOI:  https://doi.org/10.1093/hmg/ddae175
  42. PLoS Biol. 2025 Apr;23(4): e3003068
    Activation of the Drosophila innate immune system accelerates growth in cooperation with oncogenic Ras.
    Fabienne Brutscher, Federico Germani, George Hausmann, Lena Jutz, Konrad Basler.
      Innate immunity in Drosophila acts as an organismal surveillance system for external stimuli or cellular fitness and triggers context-specific responses to fight infections and maintain tissue homeostasis. However, uncontrolled activation of innate immune pathways can be detrimental. In mammals, innate immune signaling is often overactivated in malignant cells and contributes to tumor progression. Drosophila tumor models have been instrumental in the discovery of interactions between pathways that promote tumorigenesis, but little is known about whether and how the Toll innate immune pathway interacts with oncogenes. Here we use a Drosophila epithelial in vivo model to investigate the interplay between Toll signaling and oncogenic Ras. In the absence of oncogenic Ras (RasV12), Toll signaling suppresses differentiation and induces apoptosis. In contrast, in the context of RasV12, cells are protected from cell death and Dorsal promotes cell survival and proliferation to drive hyperplasia. Taken together, we show that the tissue-protective functions of innate immune activity can be hijacked by pre-malignant cells to induce tumorous overgrowth.
    DOI:  https://doi.org/10.1371/journal.pbio.3003068
  43. Blood. 2025 Apr 29. pii: blood.2024026340. [Epub ahead of print]
    The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma.
    Tommaso Perini, Paola Zordan, Rossella Del Pizzo, Massimo Resnati, Lisa Viviani, Davide Stefanoni, Laura Cassina, Ugo Paolo Orfanelli, Matteo Trudu, Laura Oliva, Daniel Lacidogna, Mehmet K Samur, Maria Materozzi, Denise Drago, Annapaola Andolfo, Marco Patrone, Massimo Degano, Alessandra Boletta, Enrico Milan, Fabio Ciceri, Nikhil C Munshi, Matteo Bellone, Simone Cenci.
      Orchestrating key homeostatic functions, mitochondria likely entail cancer vulnerabilities. Moreover, due to their bacterial ancestry they can release potent immunogenic signals. Here we show that the mitochondrial protease ClpP is both a cell-intrinsic metabolic vulnerability and an actionable immunogenic trigger in multiple myeloma (MM). We found that ClpP mRNA is higher in bone marrow (BM)-purified malignant plasma cells (PC) than in normal or premalignant counterparts and that MM lines rank first for ClpP expression among human cancers. Moreover, we demonstrated that human MM cells are highly vulnerable to ClpP inhibition in vitro and in vivo. Surprisingly, MM cell dependence on ClpP was not accounted for by its acknowledged oxidative phosphorylation surveillance activity. Proteomic discovery of proteolytic targets, metabolomics, and metabolic tracing identified a critical control exerted by ClpP on ornithine aminotransferase abundance to sustain cytosolic biosynthesis of polyamines, essential to MM cells. Transcriptomics and targeted validation also revealed activation of a cyclic GMP-AMP synthase (cGAS)-dependent type-I interferon (IFN-I) response in ClpP-silenced MM cells, whose supernatants boosted dendritic cell activation and ability to stimulate IFNg production by T cells. In vivo, ClpP silencing re-shaped the BM immune environment in immunocompetent mice, significantly expanding IFNg-producing CD4+ and CD8+ T cells and CD4+ T memory cells, while containing exhausted CD4+ T cells and myeloid derived suppressor cells. Thus, ClpP is a novel addiction of MM cells, whose inhibition not only exerts cell-intrinsic toxicity, but also triggers otherwise indolent anti-tumoral immunity. Our findings yield a novel immunogenic chemotherapeutic framework of potential relevance against myeloma.
    DOI:  https://doi.org/10.1182/blood.2024026340
  44. Cell Chem Biol. 2025 Apr 28. pii: S2451-9456(25)00100-X. [Epub ahead of print]
    N-acetyl-l-cysteine averts ferroptosis by fostering glutathione peroxidase 4.
    Jiashuo Zheng, Weijia Zhang, Junya Ito, Bernhard Henkelmann, Chenxi Xu, Eikan Mishima, Marcus Conrad.
      N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.
    Keywords:  FSP1; GPX4; GSH; NAC; cysteine; d-NAC; ferroptosis; system x(c)(−); xCT; β-ME
    DOI:  https://doi.org/10.1016/j.chembiol.2025.04.002
  45. bioRxiv. 2025 Apr 10. pii: 2025.04.09.647926. [Epub ahead of print]
    Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
    Sara Violante, Aye Kyaw, Lana Kouatli, Kaushik Paladugu, Lauren Apostolakis, Macy Jenks, Amy Johnson, Ryan D Sheldon, Anthony L Schilmiller, Pablo E Visconti, Justin R Cross, Lonny R Levin, Jochen Buck, Melanie Balbach.
      Prior to ejaculation, sperm are stored in the epididymis in a 'resting' metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13 C stable isotope labeling to follow glucose metabolism through sperm central carbon metabolic network before and after sperm activation. We identify regulatory steps which sperm use to alter their metabolic state from resting to highly active. In activated sperm, glucose flux through glycolysis is increased at the expense of the pentose phosphate pathway to increase energy yield. Increased glycolytic activity seems to be due to capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the TCA cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the tail, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase. Reduction to lactate regenerates oxidized NAD + ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating sperm.
    Significance statement: A rapid switch from a quiescent to a high energy-demanding state during ejaculation is essential for sperm to reach and fertilize the oocyte. Somatic cells also undergo bioenergetic switches from low to very high energy demand. However, because metabolic processes essential for proliferation are going on in parallel, it is difficult to identify the molecular mechanisms regulating the increase in ATP production. This study represents the first complete picture of the metabolic reprogramming that happens in sperm upon ejaculation. Using stable isotope labeling, we identify rate-limiting enzymatic steps and points of regulation directing the changes in metabolic flux. Our sperm metabolic studies allow us to identify conserved mechanisms of metabolic regulation that are crucial for the survival of mammalian cells.
    DOI:  https://doi.org/10.1101/2025.04.09.647926
  46. Nature. 2025 Apr 25.
    This is not the new colour that scientists have created.
    Elizabeth Gibney, Shamini Bundell, Dan Fox.
      
    Keywords:  Biophysics
    DOI:  https://doi.org/10.1038/d41586-025-01319-1
  47. Res Sq. 2025 Apr 08. pii: rs.3.rs-6321321. [Epub ahead of print]
    Glucuronidation Metabolomic Fingerprinting to Map Host-Microbe Metabolism.
    Andrew Patterson, Nina Boyle, Josh John, Mingxun Wang, Helena Mannochio-Russo, Jeong Joo Pyo, Min Soo Kim, Shuchang Tian, Imhoi Koo, Mallappa Anitha, Yuan Tian, Ethan Morgan, Iain Murray, Gary Perdew, Gary Wu, Pieter Dorrestein, Jordan Bisanz, Matthew Redinbo.
      Glucuronidation is an important detoxification pathway that operates in balance with gastrointestinal microbial β-glucuronidase (GUS) enzymes that can regenerate active metabolites from their glucuronidated forms. Although significant progress has been made in characterizing GUS enzymes, methods to comprehensively define the glucuronidome - the collection of glucuronidated metabolites - remain limited. In this study we employed pattern-filtering data science approaches alongside untargeted LC-MS/MS metabolomics to map the glucuronidome in urine, serum, and colon/fecal samples from gnotobiotic and conventional mice. Our findings reveal microbiome-driven shifts in the glucuronidome, highlighting how differential GUS activity can influence host metabolite profiles. Reverse metabolomics of known glucuronidated chemicals and glucuronidation pattern filtering searches in public metabolomics datasets exposed the diversity of glucuronidated metabolites in human and mouse ecosystems. In summary, we present a new glucuronidation fingerprint resource that provides broader access to and analysis of the glucuronidome. By systematically capturing glucuronidation patterns, this resource enhances unknown metabolite annotation efforts and provides new insights into the dynamic relationship between the host and bacterial biotransformation activities.
    DOI:  https://doi.org/10.21203/rs.3.rs-6321321/v1
  48. Nature. 2025 Apr 30.
    Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis.
    Sangkyun Cho, Siyeon Rhee, Christopher M Madl, Arianne Caudal, Dilip Thomas, Hyeonyu Kim, Ana Kojic, Hye Sook Shin, Abhay Mahajan, James W Jahng, Xi Wang, Phung N Thai, David T Paik, Mingqiang Wang, McKay Mullen, Natalie M Baker, Jeremy Leitz, Souhrid Mukherjee, Virginia D Winn, Y Joseph Woo, Helen M Blau, Joseph C Wu.
      Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1-6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7-10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.
    DOI:  https://doi.org/10.1038/s41586-025-08945-9
  49. Nat Commun. 2025 Apr 26. 16(1): 3934
    p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer.
    Irene Herranz-Montoya, Mariana Angulo-Aguado, Cristian Perna, Sladjana Zagorac, Luis García-Jimeno, Solip Park, Nabil Djouder.
      Incidence of colorectal cancer (CRC) is increasing likely due to different mechanisms driving initiation and progression. The initial model proposed by Fearon and Vogelstein posits it as a multi-hit neoplasia, originating from adenomatous-polyps induced by WNT activation, ultimately progressing to aggressiveness through p53 loss. Integrating human data with mouse genetics, we redefine this paradigm, highlighting pivotal roles of MYC, oncogenic URI and p53 degradation to initiate CRC. Early APC loss activates MYC to transcriptionally upregulate URI, which modulates MDM2 activity, triggering p53 proteasomal degradation, essential for tumour initiation and mutation burden accrual in CRC mice. Remarkably, reinstating p53 levels via genetic URI depletion or p53 super-expression in CRC mice with WNT pathway activation prevents tumour initiation and extends lifespan. Our data reveal a "two-hit" genetic model central to APC loss-driven CRC initiation, wherein MYC/URI axis intricately controls p53 degradation, offering mechanistic insights into transitional mutation acquisition essential for CRC progression.
    DOI:  https://doi.org/10.1038/s41467-025-59282-4
  50. Synth Biol (Oxf). 2025 ;10(1): ysaf004
    Two highly specific growth-coupled biosensor for glycolaldehyde detection across micromolar and millimolar concentrations.
    Paul A Gómez-Coronado, Armin Kubis, Maria Kowald, Rahma Ute, Charlie Cotton, Steffen N Lindner, Arren Bar-Even, Tobias J Erb.
      Glycolaldehyde (GA), the smallest sugar, has significant potential as a biomass-derived platform chemical and is a key metabolite in several synthetic pathways for one-carbon metabolism and new-to-nature photorespiration. This study introduces two metabolic schemes for engineering Escherichia coli into GA biosensors. Through creating GA-dependent auxotrophies, we link growth of these strains to GA-dependent biosynthesis of the essential vitamin pyridoxal-5-phosphate, and 2-ketoglutarate, respectively. We characterized and optimized these strains for the quantification of externally added GA from 2 µM to 1.5 mM. We also demonstrate the capability of these strains to detect GA that is produced intracellularly through different metabolic routes and from different substrates such as xylose, ethylene glycol, and glycolate. Our biosensors offer complementary sensitivities and features, opening up different applications in metabolic engineering and synthetic biology, which we demonstrate in a proof-of-principle by providing the first in vivo demonstration of the reduction of glycolate to GA by a new-to-nature route using engineered enzymes.
    Keywords:  ethylene glycol; glycolaldehyde detection; microbial biosensor; synthetic metabolism
    DOI:  https://doi.org/10.1093/synbio/ysaf004
  51. Cancer Res. 2025 Apr 28. OF1-OF13
    Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.
    Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Fan Yang, Nabil F Saba, Yong Teng.
      The tricarboxylic acid (TCA) cycle is often rewired or dysregulated to meet the increased energy and biosynthetic demands of rapidly dividing cancer cells, and targeting the TCA cycle is a potential therapeutic strategy for treating cancer. However, tumor cell metabolism can impact other cells in the tumor microenvironment, and disrupting the TCA cycle in cancer cells could impact the antitumor immune response. In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell-mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC). Impairment of mitochondrial metabolism by CPI-613 induced endoplasmic reticulum stress in HNSCC cells, leading to increased expression of spliced X-box-binding protein 1. This, in turn, directly suppressed the transcriptional activity of the thrombospondin-2 gene. Correspondingly, CPI-613 reduced the secretion of thrombospondin-2 from HNSCC cells, enhancing the proliferation and cytotoxic potential of tumor-infiltrating CD36+CD8+ T cells by upregulating AKT-mTOR signaling. This mechanism ultimately enhanced antitumor immunity in a syngeneic mouse model of orthotopic HNSCC following CPI-613 treatment. These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3477
  52. bioRxiv. 2025 Apr 08. pii: 2025.04.07.647691. [Epub ahead of print]
    Isotope tracing-based metabolite identification for mass spectrometry metabolomics.
    Deniz Secilmis, Arjana Begzati, Nina Grankvist, Irena Roci, Jeramie Watrous, Amit R Majithia, Gordon I Smith, Samuel Klein, Mohit Jain, Roland Nilsson.
      Modern mass spectrometry-based metabolomics is a key technology for biomedicine, enabling discovery and quantification of a wide array of biomolecules critical for human physiology. Yet, only a fraction of human metabolites have been structurally determined, and the majority of features in typical metabolomics data remain unknown. To date, metabolite identification relies largely on comparing MS 2 fragmentation patterns against known standards, related compounds or predicted spectra. Here, we propose an orthogonal approach to identification of endogenous metabolites, based on mass isotopomer distributions (MIDs) measured in an isotope-labeled reference material. We introduce a computational measure of pairwise distance between metabolite MIDs that allows identifying novel metabolites by their similarity to previously known peaks. Using cell material labeled with 20 individual 13 C tracers, this method identified 62% of all unknown peaks, including previously never seen metabolites. Importantly, MID-based identification is highly complementary to MS 2 -based methods in that MIDs reflect the biochemical origin of metabolites, and therefore also yields insight into their synthesis pathways, while MS 2 spectra mainly reflect structural features. Accordingly, our method performed best for small molecules, while MS 2 -based identification was stronger on lipids and complex natural products. Among the metabolites discovered was trimethylglycyl-lysine, a novel amino acid derivative that is altered in human muscle tissue after intensive lifestyle treatment. MID-based annotation using isotope-labeled reference materials enables identification of novel endogenous metabolites, extending the reach of mass spectrometry-based metabolomics.
    DOI:  https://doi.org/10.1101/2025.04.07.647691
  53. Immunity. 2025 Apr 23. pii: S1074-7613(25)00165-7. [Epub ahead of print]
    B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8+ T cell function.
    Nastaran Fazel Modares, Liam D Hendrikse, Logan K Smith, Michael St Paul, Jillian Haight, Ping Luo, Shaofeng Liu, Jerome Fortin, Frances K Tong, Andrew C Wakeham, Soode Moghadas Jafari, Chunxing Zheng, Mackenzie Buckland, Robert Flick, Jennifer Silvester, Thorsten Berger, Troy Ketela, Simone Helke, Erica Foffi, Raheleh Niavarani, Ryan Mcwilliam, Mary E Saunders, Isabelle Colonna, Bruna Araujo David, Tashi Rastogi, Woo-Yong Lee, Paul Kubes, Tak W Mak.
      Liver regeneration (LR) is essential for recovery from acute trauma, cancer surgery, or transplantation. Neurotransmitters such as acetylcholine (ACh) play a role in LR by stimulating immune cells and augmenting hepatocyte proliferation, but the source of this ACh remains unclear. Here, we demonstrated that B cells expressing choline acetyltransferase (ChAT), which synthesizes ACh, were required for LR. Mice lacking ChAT+ B cells subjected to partial hepatectomy (PHX) displayed greater mortality due to failed LR. Kupffer cells and hepatic CD8+ T cells expressed the α7 nicotinic ACh receptor (nAChR), and LR was disrupted in mice lacking α7 nAChR. Mechanistically, B cell-derived ACh signaled through α7 nAChR to positively regulate the function of regenerative Kupffer cells and to control the activation of hepatic CD8+ T cells to curtail harmful interferon-gamma (IFNγ) production. Our work offers insights into LR mechanisms that may point to therapies for liver damage.
    Keywords:  B cells; CD8 T cells; ChAT B cells; IL-6; Kupffer cells; acetylcholine; hepatic repair; liver regeneration; partial hepatectomy; α7 nAChR; α7 nicotinic acetylcholine receptor
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.002
  54. Aging Cell. 2025 Apr 30. e70089
    Immune Resilience: Rewriting the Rules of Healthy Aging.
    Monty Montano.
      Aging is typically framed by disease, not resilience. This Perspective highlights immune resilience (IR) as a core determinant of healthy aging, based on new findings linking TCF7-driven immune profiles to extended healthspan and lifespan. IR buffers against immunosenescence, inflammaging, and senescent cell phenotypes, with benefits most pronounced before age 70. By reframing aging around salutogenesis rather than pathogenesis, this work shifts the focus toward resilience mechanisms and composite traits preserving health.
    Keywords:  aging; centenarians; molecular biology of aging; senescence
    DOI:  https://doi.org/10.1111/acel.70089
  55. Sci Total Environ. 2025 Apr 25. pii: S0048-9697(25)01121-0. [Epub ahead of print]979 179484
    Short-term aircraft noise stress induces a fundamental metabolic shift in heart proteome and metabolome that bears the hallmarks of cardiovascular disease.
    Jair G Marques, Marin Kuntic, Roopesh Krishnankutty, Giovanny Rodriguez Blanco, Mykyta Malkov, Katie Frenis, Jimi Wills, Engy Shokry, Frederic Li Mow Chee, Cormac T Taylor, Thomas Munzel, Andreas Daiber, Alex von Kriegsheim.
      Environmental stressors in the modern world can fundamentally affect human physiology and health. Exposure to stressors like air pollution, heat, and traffic noise has been linked to a pronounced increase in non-communicable diseases. Specifically, aircraft noise has been identified as a risk factor for cardiovascular and metabolic diseases, such as arteriosclerosis, heart failure, stroke, and diabetes. Noise stress leads to neuronal activation with subsequent stress hormone release that ultimately activates the renin-angiotensin-aldosterone system, increases inflammation and oxidative stress thus substantially affecting the cardiovascular system. However, despite the epidemiological evidence of a link between noise stress and metabolic dysfunction, the consequences of exposure at the molecular, metabolic level of the cardiovascular system are largely unknown. Here, we use a murine model system of short-term aircraft noise exposure to show that noise stress profoundly alters heart metabolism. Within 4 days of noise exposure, the heart proteome and metabolome bear the hallmarks of reduced potential for generating ATP from fatty-acid beta-oxidation, the tricarboxylic acid cycle, and the electron transport chain. This is accompanied by the increased expression of glycolytic metabolites, including the end-product, lactate, suggesting a compensatory shift of energy production towards anaerobic glycolysis. Intriguingly, the metabolic shift is reminiscent of what is observed in failing and ischaemic hearts. Mechanistically, we further show that the metabolic rewiring is likely driven by reactive oxygen species (ROS), as we can rescue the phenotype by knocking out NOX-2/gp91phox, a ROS inducer, in mice. Our results suggest that within a short exposure time, the cardiovascular system undergoes a fundamental metabolic shift that bears the hallmarks of cardiovascular disease. These findings underscore the urgent need to comprehend the molecular consequences of environmental stressors, paving the way for targeted interventions to mitigate health risks associated with chronic noise exposure in modern, environments heavily disturbed by noise pollution.
    Keywords:  Cardiovascular; Metabolism; Noise stress
    DOI:  https://doi.org/10.1016/j.scitotenv.2025.179484
  56. Elife. 2025 Apr 29. pii: RP97671. [Epub ahead of print]13
    Microglia aging in the hippocampus advances through intermediate states that drive activation and cognitive decline.
    Jeremy M Shea, Saul A Villeda.
      During aging, microglia - the resident macrophages of the brain - exhibit altered phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFβ1 and translational states using pharmacological approaches in vitro to reveal their modulation of the progression to an activated state. Furthermore, we utilized single-cell RNA-Seq in conjunction with in vivo adult microglia-specific Tgfb1 conditional genetic knockout mouse models to demonstrate that microglia advancement through intermediate aging states drives transcriptional inflammatory activation and hippocampal-dependent cognitive decline.
    Keywords:  aging; cognition; hippocampus; immunology; inflammation; microglia; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.97671
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